The aim of this research program is to study sleep using functional neuroimaging in order to increase our understanding of the neurobiology of mental disorders such as depression. Prior studies from this program showed that there is a hierarchical neural network that regulates arousal and that may function abnormally across a variety of neuropsychiatric disorders such as depression and insomnia. In depression, a ventral limbic and paralimbic system is abnormally overactive in REM sleep and a dorsal executive system including the prefrontal cortex is abnormal in NREM sleep. We hypothesize that the effects of depression on increasing ventral neural system function in REM sleep is partially mediated by an increase in ventral neural system (amygdale/sugenual anterior cingulated cortex) fMRI responses to emotional stimuli. Second, given a substantive literature supporting a role for NREM sleep in restoring prefrontal cortex function, we hypothesize that the effects of depression on decreased prefrontal cortex function, as measured by fMRI cognitive probes, is in part mediated by the lack of restoration of the prefrontal cortex during NREM sleep in depressed patients. In the research plan of this K24 application (EA Nofzinger, PI, MH61566), we will assess cerebral metabolic responses to waking, REM and NREM sleep probes using [18F]-FDG PET and cerebral blood flow responses to affective and cognitive challenges using fMRI in 35 depressed and 35 age- and gender-matched healthy subjects. Additionally, findings of cerebral hypermetabolism during NREM sleep in insomnia, and a failure to deactivate the prefrontal cortex from waking to NREM sleep in depressed and insomnia patients raise the possibility that a hypothermic stimuli to the scalp over the area of the prefrontal cortex may decrease metabolism and facilitate sleep in these populations. Career development activities to further this line of investigation focus on two areas: 1) training in MR morphometry, fMRI and the analysis of complex multimodal imaging data;and 2) training in the use and mechanisms of cerebral hypothermia that may have applicability to sleep disordered patients. The goals of mentoring activities are to recruit and mentor at least one new trainee per year from the ranks of medical students, residents, or post-doctoral fellows. Success in mentoring will be measured by trainee's productivity in peer-reviewed publications, presentations of research at scientific meetings, and pursuit of independent career development awards and funding proposals. The principal investigator will mentor trainees in conducting patient oriented research, including the development of IRB approved protocols, implementing a research plan, and interpreting and presenting data. Content areas for mentoring young investigators include functional neuroimaging methods for use during sleep, the neuroscience of behavioral state regulation and in the ethical conduct of research.